Role of Endothelial Dysfunction in Atherosclerosis

Davignon, Jean; Gänz, Peter

doi:10.1161/01.cir.0000131515.03336.f8

Cited by 1,913 publications

(1,687 citation statements)

References 76 publications

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“…Similar findings have been previously reported in children with type 1 diabetes mellitus; endothelial dysfunction was reported in the absence of structural atherosclerotic changes (37). Previous studies in various populations have shown that endothelial dysfunction is detected long before the angiographic appearance of atherosclerosis on the vessel wall (22) and has been reported to predict the progression of carotid IMT (38). It could be speculated that JIA may be primarily associated with endothelial dysfunction, apparent even at ages 7-10 years, independently of the presence of systemic or nonsystemic disease.…”

Section: Discussionsupporting

confidence: 89%

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Changes in vascular function and structure in juvenile idiopathic arthritis

Vlahos¹,

Theocharis²,

Bechlioulis³

et al. 2011

Arthritis Care & Research

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Objective. Chronic inflammatory diseases in adults have been associated with increased cardiovascular risk and impaired vascular function. We aimed to assess the presence of early vascular dysfunction in patients with juvenile idiopathic arthritis (JIA) and investigate the role of inherent inflammatory process of JIA in vascular health. Methods. Thirty patients with JIA (age range 7-18 years) were compared to 33 age-and sex-matched controls. Endothelial function (brachial artery flow-mediated dilation [FMD]), carotid intima-media thickness (IMT), and arterial stiffness were examined. Endothelial inflammation was assessed by intercellular adhesion molecule 1 (ICAM-1) and P-selectin measurements. Results. Patients with JIA showed decreased FMD compared to controls (P ‫؍‬ 0.001), independent of age (P ‫؍‬ 0.9 among age subgroups). Baseline differences in erythrocyte sedimentation rate, ICAM-1, and glucose between the 2 groups accounted for the difference in FMD. The presence of systemic JIA was associated with greater IMT compared to patients with oligoarticular disease, polyarticular disease, or controls (P ‫؍‬ 0.014, P ‫؍‬ 0.069, and P ‫؍‬ 0.046, respectively). The difference in IMT between systemic versus oligoarticular/polyarticular JIA was attributed to the following risk factors: age, body mass index, blood pressure, disease activity, and corticosteroids use. There were no differences in arterial stiffness indices between JIA patients and controls or between patients with systemic versus nonsystemic disease. Conclusion. Endothelial function is impaired in patients with JIA at a very young age, while IMT is increased only in the presence of systemic JIA. Vascular dysfunction may be partly attributed to the effects of disease-related characteristics (inflammation, disease activity, and medications).

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Section: Discussionsupporting

confidence: 89%

“…Endothelial dysfunction, detected early in the atherosclerotic process, is known to play an important role in the initiation and progression of atherosclerosis (22). Decreased brachial FMD has been associated with increased long-term incidence of cardiovascular events in healthy adults or CVD patients (6).…”

Section: Discussionmentioning

confidence: 99%

Changes in vascular function and structure in juvenile idiopathic arthritis

Vlahos¹,

Theocharis²,

Bechlioulis³

et al. 2011

Arthritis Care & Research

View full text Add to dashboard Cite

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“…The protective effects of NO on the cardiovascular system are well documented29, 30, 31; NO functionally inhibits platelet aggregation, leukocyte adhesion, and smooth muscle cell proliferation and maintains vascular tone, thereby maintaining cardiovascular homeostasis and preventing cardiovascular diseases 32, 33, 34. However, at the initial stage of several cardiovascular diseases, oxidative stress uncouples eNOS‐derived NO, thereby increasing ONOO‐ production, which deregulates eNOS activity and leads to disease progression 35, 36, 37, 38. Statins can effectively lower cholesterol levels and reduce cardiovascular events in patients with various risk profiles 1, 2, 3, 4, 5.…”

Section: Discussionmentioning

confidence: 99%

Asymmetric Dimethylarginine Limits the Efficacy of Simvastatin Activating Endothelial Nitric Oxide Synthase

Hsu

Zhao²,

Lin

et al. 2016

JAHA

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BackgroundAsymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide synthase (eNOS), is considered a risk factor for the pathogenesis of cardiovascular diseases. Simvastatin, a lipid‐lowering drug with other pleiotropic effects, has been widely used for treatment of cardiovascular diseases. However, little is known about the effect and underlying molecular mechanisms of ADMA on the effectiveness of simvastatin in the vascular system.Methods and ResultsWe conducted a prospective cohort study to enroll 648 consecutive patients with coronary artery disease for a follow‐up period of 8 years. In patients with plasma ADMA level ≥0.49 μmol/L (a cut‐off value from receiver operating characteristic curve), statin treatment had no significant effect on cardiovascular events. We also conducted randomized, controlled studies using in vitro and in vivo models. In endothelial cells, treatment with ADMA (≥0.5 μmol/L) impaired simvastatin‐induced nitric oxide (NO) production, endothelial NO synthase (eNOS) phosphorylation, and angiogenesis. In parallel, ADMA markedly increased the activity of NADPH oxidase (NOX) and production of reactive oxygen species (ROS). The detrimental effects of ADMA on simvastatin‐induced NO production and angiogenesis were abolished by the antioxidant, N‐acetylcysteine, NOX inhibitor, or apocynin or overexpression of dimethylarginine dimethylaminohydrolase 2 (DDAH‐2). Moreover, in vivo, ADMA administration reduced Matrigel plug angiogenesis in wild‐type mice and decreased simvastatin‐induced eNOS phosphorylation in aortas of apolipoprotein E–deficient mice, but not endothelial DDAH‐2‐overexpressed aortas.ConclusionsWe conclude that ADMA may trigger NOX‐ROS signaling, which leads to restricting the simvastatin‐conferred protection of eNOS activation, NO production, and angiogenesis as well as the clinical outcome of cardiovascular events.

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“…Therapeutic targeting of different inflammatory pathways might be effective in preventing and treating cardiovascular diseases 35, 36, 37. The endothelium, as the key regulator of vascular homeostasis, has vasoprotective properties, including anti‐inflammatory response and vasodilation 38. Endothelial dysfunction is regarded as the primary driver of atherosclerotic disease 39.…”

Section: Discussionmentioning

confidence: 99%

Suberanilohydroxamic Acid as a Pharmacological Kruppel‐Like Factor 2 Activator That Represses Vascular Inflammation and Atherosclerosis

Yang

Liu

et al. 2017

JAHA

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BackgroundKruppel‐like factor 2 (KLF2) is an important zinc‐finger transcription factor that maintains endothelial homeostasis by its anti‐inflammatory, ‐thrombotic, ‐oxidative, and ‐proliferative effects in endothelial cells. In light of the potent vasoprotective effects of KLF2, modulating KLF2 expression or function could give rise to new therapeutic strategies to treat cardiovascular diseases.Methods and ResultsHigh‐throughput drug screening based on KLF2 promoter luciferase reporter assay was performed to screen KLF2 activators. Real‐time PCR and western blot were used to detect gene and protein expression. Identified KLF2 activator was orally administered to ApoE−/− mice to evaluate anti‐atherosclerotic efficacy. By screening 2400 compounds in the Spectrum library, we identified suberanilohydroxamic (SAHA) acid, also known as vorinostat as a pharmacological KLF2 activator through myocyte enhancer factor 2. We found that SAHA exhibited anti‐inflammatory effects and attenuated monocyte adhesion to endothelial cells inflamed with tumor necrosis factor alpha. We further showed that the inhibitory effect of SAHA on endothelial inflammation and ensuing monocyte adhesion was KLF2 dependent using KLF2‐deficient mouse lung endothelial cells or KLF2 small interfering RNA– depleted human endothelial cells. Importantly, we observed that oral administration of SAHA reduced diet‐induced atherosclerotic lesion development in ApoE−/− mice without significant effect on serum lipid levels.ConclusionsThese results demonstrate that SAHA has KLF2‐dependent anti‐inflammatory effects in endothelial cells and provide the proof of concept that KLF2 activation could be a promising therapeutic strategy for treating atherosclerosis.

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Role of Endothelial Dysfunction in Atherosclerosis

Cited by 1,913 publications

References 76 publications

Changes in vascular function and structure in juvenile idiopathic arthritis

Changes in vascular function and structure in juvenile idiopathic arthritis

Asymmetric Dimethylarginine Limits the Efficacy of Simvastatin Activating Endothelial Nitric Oxide Synthase

Suberanilohydroxamic Acid as a Pharmacological Kruppel‐Like Factor 2 Activator That Represses Vascular Inflammation and Atherosclerosis

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